Cosmetic or dermatological composition comprising an association between a compound of the N-acylaminoamide family and at least one matrix metalloproteinase inhibitor

ABSTRACT

A cosmetic or dermatological composition characterized in that it comprises an association between an elastase inhibitor compound of the N-acylaminoamide family and at least one metalloproteinase inhibiting compound.

[0001] The present invention relates to the field of cosmetic ordermatological compositions. It relates to novel cosmetic ordermatological compositions comprising an association between anelastase inhibitor compound of the N-acylaminoamide family and at leastone antagonist of the synthesis and/or of the release and/or theactivity of matrix metalloproteinases. Such a composition is preferablyadapted for improving the skin ageing and/or photoageing signs, whichcutaneous signs are, as far as some of them are concerned, directly aresult of a chronic micro-inflammatory process induced by repeated UVexposures.

[0002] The human skin consists in two compartments, i.e. a superficialcompartment, the epidermis, and a deep compartment, the derma. Thenatural human epidermis mainly comprises three cell types, which are thekeratinocytes, much in the majority, the melanocytes and the Langerhanscells. Each of such cell types contributes, by virtue of its ownfunctions, to the essential part played in the skin organism.

[0003] The derma provides a solid support to the epidermis. It is alsoits nutritive element. It consists mainly in fibroblast and oneextracellular matrix, comprising, in its turn, mainly collagen, elastinand one substance, the so-called fundamental substance, formed withcomponents synthetized by the fibroblast. It also comprises leukocytes,mastocytes or even tissue macrophages. It is also crossed by bloodvessels and nervous fibres.

[0004] It is known that during a superficial skin stress, which cannormally be from chemical, physical or bacterial origin, thekeratinocytes from the epidermis superficial layers release biologicalmediators which are adapted to attract some of the skin infiltratingcells, which are themselves responsible for maintaining a transitorylocal irritation.

[0005] Biological mediators able to be produced by the thus-stressedkeratinoyes include chemokines which are chemoattractive cytokinesresponsible for recruiting leukocytes on inflammatory sites, includingthe interleukin 8 (IL-8) which is more particularly responsible forrecruiting neutrophils.

[0006] Such cells infiltrating into the irritated or attacked areas thenrelease enzymes, amongst which me leukocyte elastase can be found. Underthe action of such enzyme among others, the extracellular backingelastic fibres in connective tissue may be altered and thereby lead to areduction of skin elasticity.

[0007] Further, it is also known that in synergy with cathepsin G, theleukocyte elastase may dissociate the epidermis integrity by enlargingthe interkeratinocyte intercellular spaces.

[0008] Thus, in the long term, the sum of the superficial skinmicro-stresses generated, for example, by a prolonged UV exposure or byirritating agents, can lead to a more or less accelerated loss of skinnatural elasticity. The array formed by the elastic fibres in theunderlying connective tissue and the extracellular spaces can then beprogressively dismantled. This results in an accelerated ageing of theskin (wrinkled and/or less supple skin) with the derma elastic arraybeing altered, as well as more accentuated wrinkles (deeper wrinkles).

[0009] Moreover, it is known that the derma resistance is also ensuredby collagen fibres. Such fibres are made of fibrils sealed to eachother, thereby forming more than ten types of various structures. Thederma resistance is also due to an entanglement of collagen fibres whichare packed one onto the other in all directions. The collagen fibrescontribute to the skin and/or mucous membrane elasticity and tonicity.

[0010] The collagen fibres are continuously renewed, but such a renewaldecreases over the age which also leads to the derma becoming thinner.This derma thinning is also due to pathological causes such as, forexample, cortcoid hormone hypersecretion, some pathologies or evenvitamin deficiencies (which is the case of vitamin C in scorbutus). Itis also recognized that extrinsic factors such as ultraviolet rays,tobacco or some treatments (Glucocorticoids, vitamin D and derivativesfor example) also have an effect on the skin and the matrix protein ratethereof, more particularly collagen.

[0011] Though very resistant, the collagen fibres are sensitive to someenzymes, the so-called collagenases. An alteration of the collagenfibres leads to the skin having a soft and wrinkled appearance, againstwhich the human being, preferring the appearance of a smooth and tenseskin, has always tried to fight.

[0012] Moreover, in menopause period, the main variations relating tothe derma are an alteration of the elastic tissue and a decrease of thecollagen rate and the derma thickness. This leads, in the menopausalwoman, to the skin and/or the mucous membranes becoming thinner. Thewoman then has the feeling of a “dry skin” or of a drawn skin and anincrease of fine wrinkles and small surface wrinkles can also benoticed. The skin exhibits a rough aspect when touched. Finally, theskin exhibits a reduced suppleness.

[0013] Upon a (chemical, physical, bacterial or neurogeneous) skinstress, the keratinocytes release biological mediators (calledchemoattractive factors) which are able to attract some inflammatorycells of the blood compartment towards the skin tissue. Such cells areresponsible for generating, and subsequently, for maintaining a localirritation.

[0014] Amongst the chemoattractive factors able to be produced by thestressed keratinocytes, the interleukin 8 (IL-8) is more specificallyresponsible for recruiting the neutrophil polynuclears. Such cellsinfiltrating into the irritated or attacked areas then release enzymes,including the leukocyte elastase and other proteases(metalloproteinases, protease serines, et.

[0015] Under the action of such enzyme, the extracellular backingelastic fibres in the connective tissue are altered. In synergy with thecathepsin G, the leukocyte elastase can also dissociate the epidermisintegrity enlarging the interkeratinocyte intercellular spaces(Ludolph-Hauser et al. Exp. Dermatol. 1999 8(1) 46-52). The leukocytoelastase has recently been incriminated in maintaining eschars and inproducing leg venous ulcers, through its fibronectin altering activity(Herrick S et al. Lab. Invest 1997(3) 281-288). The sum of the localizedalteration micro-stresses (resulting, for example, from a prolongedexposure to the sun) can result in the long term in an accelerated lossof the natural elasticity in skin. The underlying connective tissueelastic fibre and the extracellular space array is then progressivelydismantled. This accelerated alteration can be cumulated with the skinnormal ageing process which is characterized by a higher sensitivity ofthe elastic fibres to the elastase action (Stadler R & Orfanos C E Arch.Dermatol. Res. 1978 262 (1) 97-111).

[0016] It is known in the state of the art that molecules can be broughtin the skin tissue so as to slow down the alteration activity of theelastic fibres in the intercellular spaces.

[0017] But this not always satisfactory. Indeed, the fibril array iscomplex and numerous other enzyme activities can also degrade theelastin and the collagen and, as a consequence, dismantle anddisorganize, through a site distinctive from the elastin, thecollageno-elastic cutaneous array meshes. Such enzymes can includemetalloproteinases and gelatinases adapted to degrade either the nativecollagen (like MMP-1, MMP-2 and MMP-14) or the denatured collagen in theform of gelatin (like MMP-9 and MMP-2).

[0018] The technical solution according to the invention is to bring, inaddition to the regulating element of the elastase activity (theN-arylaminoamide derivative inhibiting the leukocyte elastase), one ormore active ingredients being able to regulate as well the other enzymeactivities interfering in the skin matrix array integrity, in the formof compositions.

[0019] Such a novel association can be used in care cosmeticcompositions for areas exposed to the sun (scalp, body, face, lips), incare cosmetic compositions of ulcerated areas, in tooth-pastes ormouthwash lotions and, generally, in all the so-called “skinanti-ageing” cosmetic preparations, the objective of which is to slowdown the chronobiological dismantling of backing tissues and thearchitecture of the skin matrix elements.

[0020] Consequently, the object of the invention is to provide acosmetic or dermatological composition characterized in that itcomprises an association between an elastase inhibiting compound of theN-acylaminoamide family and at least one metalloproteinase inhibitor.

[0021] It is understood by “metalloproteinase inhibitor” according tothe invention meaning, an antagonist compound for the synthesis and/orthe release and/or the activity of the matrix metalloproteinases.

[0022] Another object of the invention is to provide a cosmetic treatingmethod for body or face skin, including the scalp, wherein a cosmeticcomposition such as defined hereunder is applied onto the skin.

[0023] In fact, it has been found that the compounds of the formula (I)showed an inhibiting activity of the elastase activity and that they canconsequently be used for limiting and/or fighting against the elasticfibre alteration.

[0024] Therefore, they can be used in or for preparing a composition,the compounds or the composition being adapted to treat, in a preventiveand/or curative way, the ageing skin signs.

[0025] The novel association of the N-acylaminoamides with at least onemetalloproteinase inhibitor makes it possible to significantly reinforcethe anti-ageing effect of the matrix tissue by addition of an effectboth on the enzymes involved in the elastin degradation and on theenzymes involved in the collagen degradation.

[0026] According to the invention, the regulating element of theelastase activity (i.e. the N-Acylaminoamide derivative inhibitor of theenzyme activity of the leukocyte elastase), the{2-[acetyl-(3trifluorometyl-phenyl)-amino]-3-methylbutyrylamino}aceticacid is combined with one or more actives able to inhibit the activity,the synthesis or the release of the skin metalloproteinases.

[0027] The resulting composition is adapted to treat ageing disordersand/or to be more specifically designed to treat all the signs of skinageing and/or photoageing.

[0028] More preferably, this novel association is used in care cosmeticpreparations of the areas exposed to the sun (scalp, body, face, lips),and, generally, in all the so-called “skin anti-ageing” cosmeticpreparations with the objective of slowing down the dismantling of thebacking tissues and the architecture of the skin matrix elements.

[0029] Without being bound by any theory, the Applicant thinks thatbringing, at the level of the skin superficial layer keratinocytes,compounds able to slow dawn the altering activity of the intercellularspace elastic fibres, makes it possible to reduce this skin acceleratedageing phenomenon, resulting from superficial skin stresses and that theassociation of such compounds with a metalloproteinase inhibitorconsiderably reinforces their effects.

[0030] Preferred N-acylaminoamide Compounds

[0031] The compounds likely to be used in the present invention havetherefore the following formula (I):

[0032] where:

[0033] the Y radical represents O or S,

[0034] the R¹ radical represents:

[0035] (i) a hydrogen atom,

[0036] (ii) a linear, branched or cyclic, saturated or unsaturatedhydrocarbon radical having 1 to 18 carbon atoms,

[0037] optionally substituted by 1 to 5 groups, either identical ordifferent, selected amongst —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂;—NHR; —NRR′; —NH—COR; Hal (halogen); —CN; —COOR; —COR; —P(O)—(OR)₂;—SO₂—OR; with R and R′ representing, independently from each other, alinear, branched or cyclic, saturated or unsaturated hydrocarbon radicalhaving 1 to 6 carbon atoms, optionally being halogenated or evenperhalogenated;

[0038] said R and R′ radicals being able to form together with N acarbon ring with 5 to 6 ring members optionally comprising further atleast one heteroatom being selected amongst O, N and/or S in the ringand/or optionally substituted by 1 to 5 groups, identical or differentselected amongst OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″;—NH—COR″; -Hal (halogen); —CON; —COOR″; —COR″; with R″ representing alinear, branched or cyclic, saturated or unsaturated hydrocarbonradical, having 1 to 6 carbon atoms, optionally being halogenated, evenperhalogenated;

[0039] (iii) a radical selected amongst —OR; —NH₂; —NHR; —NRR′; —NH—COR;—COOR; —COR;

[0040] with R and R′ representing, independently from each other, alinear, branched or cyclic, saturated or unsaturated hydrocarbon radicalhaving 1 to 6 carbon atoms, optionally being halogenated, evenperhalogenated;

[0041] said R and R′ radicals being able to form together with N acarbon ring with 5 to 6 ring members optionally comprising,additionally, at least one heteroatom selected amongst O, N and/or S inthe ring and/or optionally substituted by 1 to 5 groups, identical ordifferent, selected amongst —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″;—NH₂; —NHR″; —NH—COR″; -Hal,(halogen); —CN; —COOR″; —COR″;

[0042] with R″ representing a linear, branched or cyclic, saturated orunsaturated hydrocarbon radical having 1 to 6 carbon atoms, optionallybeing halogenated, even perhalogenated;

[0043] the R² radical represents a linear, branched or cyclic, saturatedor unsaturated hydrocarbon radical, with 1 to 18 carbon atoms,optionally substituted by 1 to 5 groups, either identical or different,selected amongst —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR; —NRR′;—NH—COR; Hal (halogen); —CN; —COOR; —COR; with R and R′ representing,independently from each other, a hydrocarbon, straight, branched orcyclic, saturated or unsaturated radical, with 1 to 6 carbon atoms,optionally halogenated, or even perhalogenated; said R and R′ radicalsable to form together with N a carbon cycle with 5 to 6 chainsoptionally comprising, additionally, at least one heteroatom selectedamongst O, N and/or S in the ring and/or optionally substituted by 1 to5 groups, identical or different, selected amongst —OH; —OR″; —O—COR″;—SH; —SR″; —S—COR″; —NH₂; —NHR″; —NH—COR″; -Hal (halogen); —CN; —COOR″;—COR″; with R″ representing a linear, branched or cyclic, saturated orunsaturated hydrocarbon radical, with 1 to 6 carbon atoms, optionallyhalogenated, even perhalogenated;

[0044] the R³ radical represents a radical selected amongst those of theformulae (II) or (III):

-A-C₆H_((5-y))-B_(y)  (II)

—C₆H_((5-y′))-B_(y′)  (III)

[0045] where:

[0046] y is an integer between 0 and 5 inclusive, and y′ is an integerbetween 1 and 5 inclusive;

[0047] A is a linear or branched, saturated or unsaturated hydrocarbondivalent radical, with 1 to 18 carbon atoms, optionally beingsubstituted by 1 to 5 groups, either identical or different, selectedamongst —OH; —OR; —O—COR; —SH; —SR; S—COR; —NH₂; —NHR; —NRR′; —NH—COR;Hal (halogen or even perhalogen); —CN; —COOR; —COR; —NO₂; —SO₂OR;

[0048] with R and R′ representing, independently from each other, alinear, branched or cyclic, saturated or unsaturated hydrocarbonradical, with 1 to 6 carbon atoms, optionally being halogenated or evenperhalogenated;

[0049] said R and R′ radicals being able to form together with N acarbon ring with 5 to 6 ring members optionally comprising further atleast one heteroatom selected amongst O, N and/or S in the ring and/oroptionally substituted by 1 to 5 groups, identical or different,selected amongst —OH; —OR″; —O—COR″; —SH; SR″; —S—COR″; —NH₂; —NHR″;—NH—COR″; -Hal (halogen); —CN; —COOR″; —COR″; with R″ representing alinear, branched or cyclic, saturated or unsaturated hydrocarbon radicalhaving 1 to 6 carbon atoms, optionally being halogenated, evenperhalogenated;

[0050] B is a linear or branched, saturated or unsaturated hydrocarbonradical having 1 to 18 carbon atoms, optionally substituted by 1 to 5groups, either identical or different, selected amongst —OH; —OR;—O—COR; —SH; —SR; —S—COR; —NH₂; —NHR; —NRR′; —NH—COR; Hal (halogen oreven perhalogen); —CN; —COOR; —COR; —NO₂; —SO₂OR;

[0051] with R and R′ representing, independently from each other, alinear, branched or cyclic, saturated or unsaturated hydrocarbon radicalhaving 1 to 6 carbon atoms, optionally being halogenated or evenperhalogenated;

[0052] said R and R′ radicals being able to form together with N acarbon ring with 5 to 6 ring members optionally comprising further atleast one heteroatom selected amongst O, N and/or S in the ring and/oroptionally substituted by 1 to 5 groups, identical or different,selected amongst —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″;—NH—COR″; -Hal (halogen); —CN; —COOR″; —COR″; with R″ representing alinear, branched or cyclic, saturated or unsaturated hydrocarbon having1 to 6 carbon atoms, optionally being halogenated or evenperhalogenated;

[0053] the X radical is a radical selected amongst —OH; —OR₄; —NH₂;—NHR₄; —NR₄R₆; —SR₄; —COOR₄; —COR₄;

[0054] with R₄ and R₅ representing, independently from each other, alinear, cyclic or branched, saturated or unsaturated hydrocarbon radicalhaving 1 to 6 carbon atoms, optionally substituted by 1 to 5 groups,identical or different, selected amongst —OH; —OR; —O—COR; —SH; —SR;—S—COR; —NH₂; —NHR; —NH—COR; -Hal (halogen, even perhalogen); —CN;—COOR; —COR; with R and R′ representing, independently from each other,a linear, branched or cyclic, saturated or unsaturated hydrocarbonradical having 1 to 6 carbon atoms, optionally being halogenated or evenperhalogenated; said R and R′ radicals being able to form together withN a carbon ring with 5 to 6 ring members optionally comprising furtherat least one heteroatom selected amongst O, N and/or S in the ringand/or optionally substituted by 1 to 5 groups, identical or different,selected amongst —OH; —OR″; —O—COR″; —SH; —SR″; S—COR″; —NH₂; —NHR″;—NH—COR″; -Hal (halogen); —CN; —COOR″; —COR″; with R″ representing alinear, branched or cyclic, saturated or unsaturated hydrocarbon radicalhaving 1 to 6 carbon atoms, optionally being halogenated or evenperhalogenated; said R₄ and R₅ radicals being able to form together withN a carbon ring with 5 to 6 ring members optionally comprising furtherat least one heteroatom selected amongst O, N and/or S in the ringand/or optionally substituted by 1 to 5 groups, identical or different,selected amongst —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″;—NH—COR″; -Hal (halogen); —CN; —COOR″; —COR″; with R″ representing alinear, branched or cyclic, saturated or unsaturated hydrocarbon radicalhaving 1 to 6 carbon atoms, optionally being halogenated or evenperhalogenated.

[0055] Are also included in such definition, the mineral or organic acidsalts of said compounds, as well as the optical isomers thereof, in anisolated form or as a racemic mixture.

[0056] It is meant by a linear, cyclic or branched hydrocarbon radical,amongst others radicals of the alkyl, aryl, aralkyl, alkylaryl, alkenylor alkynyl type.

[0057] The C₆H₅ group present in the R₃ radical should be understood asan aromatic cyclic group.

[0058] Preferably, the Y radical represents oxygen.

[0059] Preferably, the R₁ radical represents hydrogen or a linear orbranched, saturated or unsaturated hydrocarbon radical having 1 to 12,more particularly 1, 2, 3, 4, 5 or 6 carbon atoms, optionally beingsubstituted. Amongst others, the substituants can be selected amongst—OH; —OR; and/or —P(O)—(OR)₂ with R representing a linear, branched orcyclic, saturated or unsaturated hydrocarbon radical having 1 to 6carbon atoms, optionally being halogenated, even perhalogenated.

[0060] More preferably, the R₁ radical represents a methyl, ethyl,propyl or isopropyl radical optionally substituted by a —OH or—P(O)—(OR)₂ group with R representing methyl, ethyl, propyl orisopropyl.

[0061] Preferably, the R₂ radical represents a linear, branched orcyclic, saturated or unsaturated hydrocarbon radical having 1 to 12,more particularly, 1, 2, 3, 4, 5 or 6 carbon atoms, optionallysubstituted.

[0062] Amongst others, the substituants can be selected amongst —OH and—OR with R representing a linear, branched or cyclic, saturated orunsaturated hydrocarbon radical having 1 to 6 carbon atoms, optionallybeing halogenated, even perhalogenated.

[0063] More preferably, the R₂ radical represents a methyl, ethyl,propyl, isopropyl, n-butyl, ter-butyl or isobutyl radical.

[0064] Preferably, the R₃ radical represents a radical of the formula—C₆H_((5-y′))-B_(4′) where y′=1, 2 or 3; or a radical of the formula-A-C₆H_((5-y))-B_(y) where y=0, 1 or 2.

[0065] Preferably, A is a linear or branched, saturated or unsaturatedhydrocarbon divalent radical having 1 to 12 carbon atoms, optionallysubstituted.

[0066] The substituants for A are preferably selected amongst -Hal(halogen, even perhalogen); —CN; —COOR; —NO₂; —SO₂—OR; with Rrepresenting a linear, branched or cyclic, saturated or unsaturatedhydrocarbon radical having 1 to 6 carbon atoms, optionally beinghalogenated, even perhalogenated.

[0067] Preferably, B is a linear or branched, saturated or unsaturatedhydrocarbon radical having 1 to 12 carbon atoms, optionally substituted.

[0068] The substituants for B are preferably selected amongst -Hal(halogen, even perhalogen); —CN; —COOR; —NO₂; —SO₂—OR; with Rrepresenting a linear, branched or cyclic, saturated or unsaturatedhydrocarbon radical having 1 to 6 carbon atoms, optionally beinghalogenated, even perhalogenated.

[0069] More preferably, the R₃ radical is a group selected amongst oneof the following formulae:

[0070] where A and B have the meanings as hereabove.

[0071] More particularly, the divalent A radical can be a methylene, anethylene, a propylene.

[0072] The B radical is preferably a methyl, ethyl, propyl or isopropylradical, substituted by one or more halogens, more particularlychlorine, bromine, iodine or fluorine, and more preferably completelyhalogenated (perhalogenated) such as perfluorinated. The most preferredone is in particular the perfluoromethyl radical (—CF₃).

[0073] More preferably, the X radical represents a radical selectedamongst —OH or —OR₄ with R₄ representing a linear, cyclic or branched,saturated or unsaturated hydrocarbon radical having 1 to 6 carbon atoms,optionally substituted.

[0074] The substituants can be selected amongst —OH and —OR with Rrepresenting a linear, branched or cyclic, saturated or unsaturatedhydrocarbon radical having 1 to 6 carbon atoms, optionally beinghalogenated, even perhalogenated.

[0075] More preferably, the X radical represents a radical selectedamongst —OH, —OCH₃, —OC₂H₅, —O—C₃H₇ or —C₄H₉.

[0076] The particularly preferred compounds include:

[0077]{2-[acetyl-(3-trifluoromethyl-phenyl)-amino]-3-méthyl-butyrylamino}aceticacid,

[0078]{2-[acetyl-(3-trifluoromethyl-phenyl)-amino]-3-méthyl-butyrylamino}ethylacetate,

[0079] [2-(acetyl-benzyl-amino)-3-méthyl-butyrylamino]acetic acid,

[0080] [2-(acetyl-benzyl-amino)-3-méthyl-butyrylamino]ethyl acetate, and

[0081][2-{benzyl-[(diethoxy-phosphoryl)-acetyl]-amino}-3-méthyl-butyryl-amino]ethylacetate.

[0082] The compounds according to the invention can be easily preparedby the man of the art based on its general knowledge. It is moreparticularly possible to react together a carboxylic acid, an aldehyde,an amino compound and an isonitrile, according to Ugl reaction.

[0083] Obviously, upon the synthesis of the compounds according to theinvention and depending on the nature of the various radicals present onthe starting compounds, the man of the art will make sure to protectsome substituants so that they are not involved in the reactionsequence.

[0084] The compound quantity to be used in the compositions according tothe invention can be easily determined by the man of the art, dependingon the nature of the compound to be used, on the person to be treatedand/or the desired effect. Generally, this amount can range from 0.00001to 20% by weight based on the total weight of the composition,preferably 0.0001 to 5% by weight.

[0085] The compounds of the formula (I) can normally be used, in acomposition comprising a physiologically acceptable medium, including ina cosmetic or pharmaceutical composition thus additionally comprising acosmetically or pharmaceutically acceptable medium.

[0086] The physiologically acceptable medium wherein the compoundsaccording to the invention can be used, as well as the componentsthereof, their amount, the galenic form and its preparation mode, can beselected by the man of the art based on its general knowledge dependingon the desired composition type.

[0087] Generally, such a medium can be anhydrous or aqueous. It can alsocomprise an aqueous phase and/a fatty phase.

[0088] Preferred Metalloproteinase Inhibitors

[0089] It is meant by “metalloproteinase inhibitor” according to theinvention any molecule and/or vegetable or bacterial extract showing aninhibiting activity on the skin metalloproteinases.

[0090] Metalloproteinases are more particularly described in Y. HEROUYet al., European Journal of Dermatology, n° 3, vol. 10, April-May 2000,pp. 173-180.

[0091] The metalloproteinase family thus comprises several well definedgroups based on their similarities in term of structure and substratespecificity (see Woessner J. F., Faseb Journal, vol. 5, 1991, 2145).Such groups can include collagenases adapted to degrade the fibrilcollagens (MMP-1 or interstitial collagenase, MMP8 or neutrophilcollagenase, MMP-13 or collagenase 3, MMP-18 or collagenase 4),gelatinases degrading the type IV collagen or any form of denaturedcollagen (MMP-2 or gelatinase A (72 kDa), MMP-9 or gelatinase B (92kDa)), stromelysins (MMP-3 or stromelysin 1, MMP-10 or stromelysin 2,MMP-11 or stromelysin 3), the broad activity spectrum of which addressesproteins of the extracellular matrix such as glycoproteins (fibronectin,laminin), proteoglycans, etc., matrilysin (MMP-7), metalloelastase(MMP-12) or even membrane metalloproteinases (MMP-14, MMP-15, MMP-16 andMMP-17).

[0092] The metalloproteinases (MMPs) are the members of a proteolyticenzyme family (endoproteases) having a zinc atom coordinated with 3cystein residues and with a methionine in their active site anddegrading macromolecular components of the extracellular matrix andbasal lamellae at a neutral pH (collagen, elastin, etc..). Very widelyspread in the living world, such enzymes are present, but weaklyexpressed, in normal physiological situations such as organ growth andtissue renewal.

[0093] Their overexpression in man and their activation are howeverbound to numerous processes involving the matrix destruction andrestructuration. This leads, for example, to an uncontrolled resorptionof the extracellular matrix.

[0094] Thus, a prolonged exposure to ultraviolet radiations, moreparticularly to ultraviolet rays of the type A and/or B, has the effectof stimulating the collagenase expression, particularly of the MMP-1.This is one of the components of the photoinduced skin ageing. Moreover,it is known that the activity of MMP-1, MMP-2 and MMP-9 increases overthe age and that such an increase contributes, with the cell growthslowing down, to the skin chronological ageing (WO 98/36742).

[0095] The metalloproteinases are produced and secreted under aninactive form (pro-enzyme). Such inactive forms, so-called zymogens, arethen activated in the extracellular environment through elimination of apropeptid area. The members of this family can activate one another. TheMMP activity regulation occurs therefore at the level of the geneexpression (transcrption and translation), at the level of the zymogenform activity, or at the level of the local control of the active forms.

[0096] The natural regulators of the MMP activity are the tissueinhibitors of metalloproteinases or TIMPs (tissue inhibitors ofmetalloproteinases). However, the expression of the MMPs is alsomodulated by the growth factors, the cytokines, the oncogenic products(ras, jun) or even the matrix components.

[0097] It is meant by metalloproteinase inhibitor according to theinvention, any molecule being able to regulate the MMP activity eitherat the level of the gene expression (transcription and translation),either at the level of the activation of the MMP zymogen form activity,or also at the level of the local control of the active forms.

[0098] More preferably, a composition according to the invention ischaracterized in that the metalloproteinase inhibitor is selectedamongst an inhibitor of a metalloproteinase selected amongst MMP-1,MMP-2, MMP-₃, MMP-7, MMP-9, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15,MMP-16 and MMP-17. The metalloproteinase inhibitor according to theinvention can be a natural inhibitor of metalloproteinases, particularlya tissue inhibitor of the metalloproteinases (TIMP) such as peptidesknown in the prior art under the names TIMP-1, TIMP-2, TIMP-3 and TIMP-4(Woessner J. F., Faseb Journal, 1991).

[0099] Alternatively, the metalloproteinase inhibitors suitable for usein the present invention may be MMP-1 inhibitors from natural orsynthetic origin. It is meant by “natural origin”, the metalloproteinaseinhibitor in a pure state or in a solution at various concentrations,obtained by means of various exacting methods from an element, generallya plant, from natural origin. It is meant by “synthetic origin” themetalloproteinase inhibitor in a pure state or in a solution at variousconcentrations, obtained through chemical synthesis.

[0100] The metalloproteinase inhibitor can also be a natural extractcontaining ursolic acid or carotenoids or vitamin C or isoflavones likethe genistein known for its metalloproteinase inhibiting activity (U.S.Pat. No. 6,130,254).

[0101] According to a preferred embodiment of the invention, ametalloproteinase inhibitor from natural origin is used, such aslycopene or an isoflavone. The lycopene activity on themetalloproteinases have been disclosed in Patent ApplicationEP-A-1090628.

[0102] According to another preferred embodiment, the metalloproteinaseinhibitor is a MMP-1 metalloproteinase transcriptional inhibitor, suchas retinol or the derivatives thereof, retinoic acid and the derivativesthereof. The inhibitors to be associated with can also be selectedamongst retinoic acid and the derivatives thereof, adapalene or alsoanalogous peptides and/or the derivatives of Batimastat ((BB94)=[4-(N-hydroxyamino)-2R-isobutyl-3S-(thiophen-2-ylthiomethyl)-succinyl-L-phenylalanine-N-methylamide),of Marimastat ((BB 2516)=[2S-[N4(R*),2R*,3S]]-N4[2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-N1,2dihydroxy-3-(2-methylpropyl)butanediamide)sold by the British Biotech corporation or also natural biologicalinhibitors such as the tissue inhibitors of metalloproteinases (TIMPs),as well as structural and/or functional analogs, even also inducers forsynthesis and/or release of such natural inhibitors. Sunscreens, byvirtue of an indirect action on metalloproteinase transcription et/orsynthesis, are also useful according to the invention.

[0103] More preferably, a composition according to the invention willcontain retinol as a metalloproteinase inhibitor.

[0104] Ideally, it will be possible to use such a novel association incare cosmetic preparations for sun exposed areas (scalp, body, face,lips) and, generally, in all the so-called “skin anti-ageing” cosmeticpreparations with the objective of slowing down the chronobiologicaldismantling of the backing tissues and the architecture of the skinmatrix elements.

[0105] The metalloproteinase inhibitor preferably represents 10⁻¹² to5%, more preferably 10⁻¹⁰ to 2% of the total weight of the composition.Obviously, if the metalloproteinase inhibitor is present in the form ofa solution containing a plant extract, the man of the art will be ableto adjust such a solution amount in the composition of the invention, soas to obtain the expected effect on the activity and/or the synthesisand/or the release of metalloproteinases.

[0106] The association of at least one N-acylaminoamide compound and atleast one metalloproteinase inhibitor can be used, more particularly,alone or in a mixture, in a composition comprising a physiologicallyacceptable medium, in particular in a cosmetic or pharmaceuticalcomposition which, therefore, comprises a cosmetically orpharmaceutically acceptable medium.

[0107] The physiologically acceptable medium in which the compoundsaccording to the invention can be used, as well as the componentsthereof, their amount, the galenic form of the composition and itspreparation mode, can be selected by the man of the art on the basis ofits general knowledge depending on the type of the desired composition.

[0108] Generally, such a medium can be anhydrous or aqueous. It can thuscomprise an aqueous phase and/or a fatty phase.

[0109] For applying onto the skin, the composition can have the form inparticular of an aqueous or an oily solution; of a dispersion of thelotion or serum type, of emulsions of liquid or semi-liquid consistencyof the milk type obtained through dispersion of a fatty phase into anaqueous phase (O/W) or reversely (W/O); of suspensions or emulsions of asoft consistency of the cream type or aqueous or anhydrous gel type; ofmicrocapsules or microparticles; of vesicular dispersions of the ionicand/or non ionic type.

[0110] For applying on the hair, the composition can be in the form ofaqueous, alcoholic or hydroalcoholic solutions; in the form of creams,gels, emulsions, foams; in the form of aerosol compositions comprising apressurized propellant as well.

[0111] When the composition is in an aqueous form, in particular in anaqueous dispersion, emulsion or solution, it can comprise an aqueousphase, which may comprise water, flower water and/or mineral water.

[0112] Said aqueous phase can additionally comprise alcohols such asC₁-C₆ monoalcohols and/or polyols such as glycerol, butyleneglycol,isoprene glycol, propyleneglycol, polyethyleneglycol.

[0113] When the composition according to the invention is in the form ofan emulsion, it can optionally additionally comprise a surfactant,preferably in an amount ranging from 0.01 to 30% by weight based on thetotal weight of the composition. The composition according to theinvention can also comprise at least one co-emulsifier which can beselected amongst oxyethylenated sorbitan monostearate, fatty alcoholssuch as stearyl alcohol or cetyl alcohol, or esters of fatty acids andpolyols such as glyceryl stearate.

[0114] The composition according to the invention can also comprise afatty phase, in particular made of fatty bodies liquid at 25° C., suchas oils from animal, vegetable, mineral or synthetic origin, eithervolatile or not, fatty bodies solid at 25° C. such as waxes from animal,vegetable, mineral or synthetic origin; of pasty fatty bodies; of gums;and the mixtures thereof.

[0115] The volatile oils are generally oils having, at 25° C., asaturating vapor tension at least equal to 0.5 millibar (50 Pa).

[0116] Are included amongst the fatty phase components:

[0117] cyclic volatile silicones having 3 to 8 silicon atoms, preferably4 to 6,

[0118] cyclocopolymers of the dimethylsiloxane/methylalkylsiloxane type,

[0119] linear volatile silicones with 2 to 9 silicon atoms,

[0120] hydrocarbon volatile oils, such as isoparaffins and, moreparticularly, isododecane and fluorinated oils,

[0121] poly(C₁-C₂₀)alkylsiloxanes and, more particularly, those withtrimethylsilyl end groups, amongst which linear polydimethylsiloxanesand alkylmethylpolysiloxanes such as cetyldimethicone (CTFA name),

[0122] silicones modified by aliphatic and/or aromatic groups,optionally fluorinated, or by functional groups such as hydroxyl, thioland/or amine groups,

[0123] phenylated silicone oils,

[0124] oils from animal, vegetable or mineral origin, in particularanimal or plants oils made of esters of fatty acids and polyols, inparticular liquid triglycerids, for example sunflower, corn, soya,marrow, grape seed, sesame, hazelnut, apricot, almond, or avocado oils;fish oils, glycerol tricaprocaprylate, or plant or animal oils havingthe formula R₁COOR₂, where R₁ represents the residue of a superior fattyacid having 7 to 19 carbon atoms and R₂ represents a branchedhydrocarbon chain having 3 to 20 carbon atoms, for example Purcellinoil; paraffin oil, liquid paraffin, perhydrosqualene, wheatgerm,calophyllum, sesame, macadamia, grape seed, colza, copra, arachis, palm,castor, jojoba, olive or cereal germ oils; fatty acid esters; alcohols;acetylglycerides; octanoates, decanoates or ricinoleates from alcoholsor polyalcohols; fatty acid triglycerids; glycerids;

[0125] fluorinated and perfluorinated oils;

[0126] silicone gums;

[0127] waxes from animal, vegetable, mineral or synthetic origin, suchas microcrystalline waxes, paraffin, petrolatum, liquid paraffin,ozokerite, Montan wax; beewax, lanolin, and the derivatives thereof;Candelilla, Ouricury and Japan waxes, cocobutter, cork fibre or sugarcane waxes; hydrogenated oils solid at 25° C., ozokerites, fatty estersand glycerides solid at 25° C.; polyethylene waxes and waxes obtainedthrough Fischer-Tropsch synthesis; hydrogenated oils solid at 25° C.;lanolins; fatty esters solid at 25° C.; silicone waxes; fluorinatedwaxes.

[0128] As it is known, the composition according to the invention cancomprise the usual builders in the field being involved, such ashydrophilic or lipophilic gelling agents, hydrophilic or lipophilicadditives, actives, in particular hydrophilic or lipophilia cosmetic orpharmaceutical actives, preservatives, antioxidants, solvents, perfumes,fillers, pigments, nacres, UV filters, odor absorbers and colorants.Such builders, depending on their nature, can be introduced into thefatty phase, into the aqueous phase and/or into lipid spherules.

[0129] The nature and the amount of such builders can be selected by theman of the art, based on its general knowledge, so as to obtain thedesired presentation form for the composition. Anyway, the man of theart will make sure to select all the optional complementary compoundsand/or their amount, so that the advantageous properties of thecomposition according to the invention are not, or substantially not,altered by the contemplated addition.

[0130] The cosmetic or pharmaceutical compositions according to theinvention can, in particular, have the form of a composition designedfor caring and/or treating ulcerated areas or which have been subjectedto a cutaneous stress or microstress, in particular generated by anexposure to the UV and/or the contact with an irritating product.

[0131] Accordingly, the compositions according to the invention can, inparticular, exhibit the form of:

[0132] a care, treatment, cleaning or protection product for the face orthe body skin, including the scalp, such as a (day, night, hydrating)care composition for the face or the body; an anti-wrinkle oranti-ageing composition for the face; a mating composition for the face;a composition for the irritated skins; a make-up removing composition; abody milk, in particular being hydrating optionally an after-sun bodymilk;

[0133] a sun protective, artificial sun tanning (self-tanning) orafter-sun care composition;

[0134] a capillary composition, more particularly a sun protective creamor gel; a scalp care composition, including an hair restoring or hairgrowth composition; an anti-parasitic shampoo;

[0135] a face skin, body or lip makeup product, such as a foundationcream, a tinted cream, a cheek or eye-id makeup product, a free orcompact powder, an anti eye-ring stick, a concealing stick, a lipstick alip care product; and

[0136] a mouth hygiene product, such as a tooth-paste or a mouthwashlotion.

[0137] The compositions according to the invention find a preferredapplication as a composition for face skin care, of the anti-wrinkle oranti-ageing type and as a sun protective or an after-sun composition.

[0138] The object of the present invention is also to provide a methodcomprising the steps of cosmetically treating the body or the face skin,in particular, the scalp, wherein a cosmetic composition is applied ontothe skin, comprising an association between a compound of theN-acylaminoamide family and at least a metalloproteinase inhibitor,leaving it in contact and optionally rinsing.

[0139] The cosmetic treatment method according to the invention can beapplied in particular by applying cosmetic compositions such as definedhereabove, according to the usual use technique of said compositions.For example: application of creams, gels, serums, lotions, make-upremoving milks or anti-sun compositions on the skin or on dry hair;application of a scalp lotion on wet hair, application of tooth-paste onthe gums.

[0140] The invention is illustrated in further detail in the followingexamples.

EXAMPLE 1

[0141] Preparation of{2-[acetyl-(3-trifluoromethyl-phenyl)-amino]-3-méthylbuytylamino}ethylacetate of the formula:

[0142] 0.63 ml isobutyraldehyde and 1 ml trifluoromethylamine (1.15 eq)are mixed in 15 ml methanol under stirring. It is left to react for 15minutes at 20° C., thereafter 0.46 ml acetic acid are added (1.15 eq)and it is left to react for 10 minutes at 20° C. Then 0.8 ml 95% ethylisocyanoacetate (1 eq) are added and left to react for 48 hours at 20°C.

[0143] The reaction medium is concentrated using a rotovapor and theresidue is purified on a silica column (eluant: heptane: 3-ethylacetate: 7; Rf=0.5).

[0144] 2.45 g of a compound in the form of a waxy solid are obtained,whence a 91% yield.

[0145] NMR¹H (200 MHz; CDC13) δ ppm: 0-9 (6H; q), 1.3 (3H; t), 1.8 (3H;s), 2.3 (1H; m), 4.0 (2H, q), 4.2 (2H; q), 4.4 (2H; d), 7.3 (1H; t), 7.5(4H; m).

EXAMPLE 2 Preparation of{2-[acetyl-(3-trifluoromethyl-phenyl)-amino]-3-méthylbutyrylamino}aceticacid of the formula:

[0146]

[0147] 2 g of the compound prepared according to example 1 aresolubilized in 30 ml acetone. 30 ml 2N sodium hydroxyde are added andleft to react for 6 hours at 20° C. The reaction medium is concentratedusing a rotovapor. The residual aqueous phase is acidified at pH 2adding concentrated HCl and then extracted with CH₂Cl₂.

[0148] The organic phase is dry concentrated after drying on sodiumsulfate.

[0149] A residue is obtained which is solubilized with a base watermixture at 10% ethanol and then again acidified with concentrated HCl atpH 2. A new extraction by CH₂Cl₂ is performed, the organic phase isdried on sodium sulfate, filtered and dry concentrated under vacuum in arotovapor.

[0150] 1.3 g of a compound are obtained in the form of a slight lightbrown solid, whence a 70% yield.

[0151] NMR¹H (200 MHz; DMSO) δ ppm : 0.9 (6H; q), 3.7 (2H; m), 1.8 (4H,m), 4.8 (2H; d), 7.6 (4H, q), 8.4 (1H; t), 12.5 (1H; s).

EXAMPLE 3

[0152] The anti-elastasic activity of compounds according to theinvention is determined in vitro compared to the human leukocyteelastase (ELH).

[0153] The test is performed in the following way:

[0154] A Me-OSAAPV-p-NA (methyl-Ouccinate alanine alanine prolinevaline-p-nitroaniline) substrate, onto which ELH (40 milli-units per ml)and 0.1% of the compound to be tested are applied, is left forincubating at 37° C. for 60 minutes.

[0155] Thereafter, the % inhibition of the control elastase activity isdetermined by spectrophotometry,

[0156] The tested compounds are the following:

[0157] Compound A:{2-[acetyl-(3-trifluoromethyl-phenyl)-amino]-3-méthyl-butyryl-amino}aceticacid,

[0158] Compound B:(2-{benzyl-[(diethoxy-phosphoryl)-acetyl]-amino}-3-méthyl-butyryl-amino)ethylacetate,

[0159] Compound C: [2-(acetyl-benzyl-amino)-3-méthyl-butyrylamino]aceticacid,

[0160] Compound D: [2-(acetyl-benzyl-amino)-3-méthyl-butyrylamino]ethylacetate.

[0161] The following results are obtained: Compound % Inhibition of the(concentration: 0.1%) control elastase activity Compound A 67% CompoundB 17% Compound C 20% Compound D 13%

[0162] The same way, the % inhibition of the control elastase activityis determined for compound A, at various concentrations.

[0163] The following results are obtained: Compound A % Inhibition ofthe concentration control elastase activity 0.01% 53% 0.05% 50% 0.1% 68% 0.2%  68%

[0164] Compound A therefore generates a strong inhibition of theelastase activity, even in a small amount.

EXAMPLE 4

[0165] The ex vivo activity of example 2 compound has been evaluated onsurviving human skins treated by a human leukocyte elastase (ELH).

[0166] The test is performed the following way.

[0167] Fresh human skin cuts from two different donors are treated for 2hours, at 20° C., by 20 μl of a buffer solution (pH 7.4) optionallycomprising 10 μg/ml ELH and optionally 0.1% of the compound to betested, optionally previously put in solution in ethanol.

[0168] The elastic fibres are coloured in blue using ogtechin (+) andquantified morphometrically using a computer assisted image analysis.The average derma surface percentage occupied by elastic fibres isevaluated this way.

[0169] The following results are obtained: % Surface occupied by elasticfibres Skin 1 Skin 2 Control (untreated skin) 12.7% 15.25% ELH treatedskin 4.85%  6.85% ELH treated skin + 13.95% 11.85% example 2 compound

[0170] It is therefore found out that the compound according to theinvention generates a skin significant protection against thedestruction of elastic fibres induced by elastase.

EXAMPLE 5

[0171] The ex vivo activity of example 2 compound has been evaluated onsurviving human skins treated by a human leukocytelastase (ELH).

[0172] The test is performed the following way:

[0173] Fragments of normal human skin from three different donors aredeposited in inserts positioned in culture wells. Culture medium addedwith antibiotics is added in the bottom of the wells. A pass isperformed through slow diffusion between the two compartments via aporous membrane (pore size: 12 μm).

[0174] The culture medium is renewed every three days.

[0175] On the skin fragments, optionally 0.5 μg ELH per ml culturemedium are added.

[0176] 5 μl of the compound to be tested are also added every two days,previously put in solution at 0.2% by weight in ethanol.

[0177] The skins are kept surviving for 10 days at 37° C.

[0178] The elastic fibres are coloured in blue using catechin (+) andquantified morphometrically using a computer assisted image analysis.The average derma surface percentage occupied by elastic fibres isevaluated this way.

[0179] The following results are obtained: % Surface occupied by elasticfibres Control (untreated skin) 7.4% ELH treated skin 5.1% ELK treatedskin + example 2 7.1% compound

[0180] It is therefore found out that the compound according to theinvention generates a significant skin protection against thedestruction of elastic fibres induced by the elastase.

EXAMPLE 6

[0181] The activity of the example 2 compound has been evaluated onsurviving human skins irradiated by UVA (8 J/cm²).

[0182] The test is performed the following way.

[0183] Fragments of normal human skin from four different donors aredeposited in inserts positioned in culture wells. Culture medium addedwith antibiotics is added in the bottom of the wells. A pass isperformed through slow diffusion between the two compartments via aporous membrane (pore size: 12 μm).

[0184] The culture medium is renewed every three days.

[0185] On the skin fragments, every two days, 5 μl of a 0.2% solution ofthe compound to be tested are added, in solution in ethanol.

[0186] The skins are kept surviving for 7 days at 37° C.

[0187] The skins are irradiated once at 8 J/cm² (RMX-3W Vilbert-Lourmatlamp).

[0188] The elastic fibres are coloured in blue using catechin (+) andquantified morphometrically using a computer assisted image analysis.The average derma surface percentage occupied by elastic fibres isevaluated this way.

[0189] The following results are obtained: Elastic fibres Collagenmorphometric morphometric analysis analysis (superficial (superficialderma) derma) Untreated skin 6.75% 87% UVA treated skin 3.9% 81% (8J/cm²) UVA treated skin 6.8% 92% (8 J/cm²) + compound

[0190] It is found out that the compound according to the invention doeshave an activity towards the destruction of elastic fibres in the UVAirradiated skin superficial derma.

[0191] This compound also exhibits an adequate effect on the collagenprotection.

EXAMPLE 7 Composition for Topic Application

[0192] The following emulsion is prepared conventionally (% by weight):Compound from example 1  1% Retinol  0.1% Propylene glycol isostearate13% Polyethylene glyocl (8 OE)  5% Propylene glycol  3% Pentylene glycol 3% Glyceryl stearate and polyethylene glycol stearate (100 OE)  5%Oxyethylenated (20 OE) sorbitan monostearate  0.5% Oxypropylenated (20OE) oxyethylenated (5 OP) cetyl alcohol  1% Gelling agents  0.5% C₁₂-C₁₅alkyl benzoates  4% Ethanol  3% Sodium hydroxide  0.12% Preservatives qsWater qsp 100%

EXAMPLE 9 Face Care Cream

[0193] The following oil-in-water emulsion is prepared conventionally (%by weight): Example 2 compound  1% Lycopene (in the form of Lycomato ®at 10% of lycopene  0.001% in a tomato oleoresin sold by Lycored ®)Glycal stearate  2% Polysorbate 60 (Tween 6O ® sold by ICI corporation) 1% Steatic acid  1.4% Triethanolamine  0.7% Carbomer  0.4% Shea butterliquid fraction 12% Perhydrosqualene 12% Antioxidant qs Perfume qsPreservative qs Water qsp 100%

EXAMPLE 9 Face Milk

[0194] The following milk is prepared according to the conventional way(% by weight): Liquid paraffin 7% Genistein 0.2% Example 2 compound 1%Glyceryl monostearate, polyethylene glycol stearate (100 OE) 3%Carboxyvinyl polymer 0.4% Stearyl alcohol 0.7% Soya protein 3% NaOH 0.4%Preservative qs Water qsp 100%

EXAMPLE 10 Hair Lotion

[0195] The following lotion is prepared conventionally (% by weight):Example 1 compound  1% Retinol  0.01% Propylene glycol 23% Ethanol 55%Water qsp 100%

[0196] This lotion can be applied onto the scalp of alopecic people forpreventing the UV effects, before and/or after sun exposure.

EXAMPLE 11 Hair Restoring Lotion

[0197] The following lotion is prepared conventionally (% by weight):Example 2 compound  1% Lycopene (in the form of Lycomato ® at 10% oflycopene  0.0001% in a tomato oleoresin sold by Lycored ®) Propyleneglycol 23% Ethanol 55% Aminexil  1.5% Water qsp 100%

[0198] This hair restoring lotion can be applied onto the scalp ofalopecic people.

1. A cosmetic or dermatological composition characterized in that itcomprises an association between an elastase inhibitor compound of theN-acylaminoamide family and at least one metalloproteinase inhibitor. 2.A composition according to claim 1, characterized in that the compound,the inhibiting compound of the N-acylaminoamide family, is a compound ofthe formula (I):

where: the Y radical represents O or S, the R¹ radical represents: (i) ahydrogen atom, (ii) a linear, branched or cyclic, saturated orunsaturated hydrocarbon radical having 1 to 18 carbon atoms, optionallysubstituted by 1 to 5 groups, either identical or different, selectedamongst —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR; —NRR′; —NH—COR;Hal (halogen); —CN; COOR; —COR; —P(O)—(OR)₂; —SO₂—OR; with R and R′representing, independently from each other, a linear, branched orcyclic, saturated or unsaturated hydrocarbon radical having 1 to 6carbon atoms, optionally being halogenated or even perhalogenated; saidR and R′ radicals being able to form together with N a carbon ring with5 to 6 ring members optionally comprising further at least oneheteroatom being selected amongst O, N and/or S in the ring and/oroptionally substituted by 1 to 5 groups, identical or different,selected amongst —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″;—NH—COR″; -Hal (halogen); —CN; —COOR″; —COR″; with R″ representing alinear, branched or cyclic, saturated or unsaturated hydrocarbonradical, having 1 to 6 carbon atoms, optionally being halogenated, evenperhalogenated; (iii) a radical selected amongst —OR; —NH₂; —NHR; —NRR′;—NH—COR; —COOR; —COR; with R and R′ representing, independently fromeach other, a linear, branched or cyclic, saturated or insaturatedhydrocarbon radical having 1 to 6 carbon atoms, optionally beinghalogenated, even perhalogenated; said R and R′ radicals being able toform together with N a carbon ring with 5 to 6 ring members optionallycomprising, additionally, at least one heteroatom selected amongst O, Nand/or S in the ring and/or optionally substituted by 1 to 5 groups,identical or different, selected amongst —OH; —OR″; —O—COR″; —SH; —SR″;—S—COR″; —NH₂; —NHR″; —NH—COR″; -Hal (halogen); —CN; —COOR″; —COR″; withR″ representing a linear, branched or cyclic, saturated or unsaturatedhydrocarbon radical having 1 to 6 carbon atoms, optionally beinghalogenated, even perhalogenated; the R² radical represents a linear,branched or cyclic, saturated or unsaturated hydrocarbon radical, with 1to 18 carbon atoms, optionally substituted by 1 to 5 groups, eitheridentical or different, selected amongst —OH; —OR; —O—COR; —SH; —SR;—S—COR; —NH₂; —NHR; —NRR′; —NH—COR; Hal (halogen); —CN; —COOR; —COR;with R and R′ representing, independently from each other, ahydrocarbon, linear, branched or cyclic, saturated or unsaturatedradical, with 1 to 6 carbon atoms, optionally halogenated, or evenperhalogenated; said R and R′ radicals able to form together with N acarbon cycle with 5 to 6 chains optionally comprising, additionally, atleast one heteroatom selected amongst O, N and/or S in the ring and/oroptionally substituted by 1 to 5 groups, identical or different,selected amongst —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″;—NH—COR″; -Hal (halogen); —CN; —COOR″; —COR″; with R″ representing alinear, branched or cyclic, saturated or unsaturated hydrocarbonradical, with 1 to 6 carbon atoms, optionally halogenated, evenperhalogenated; the R² radical represents a radical selected amongstthose of the formulae (II) or (III)-A-C₆H_((5-y))-B_(y)  (II)—C₆H_((5-y′))-B_(y′)  (III) where: y is aninteger between 0 and 5 inclusive, and y′ is an integer between 1 and 5inclusive; A is a linear or branched, saturated or unsaturatedhydrocarbon divalent radical, with 1 to 18 carbon atoms, optionallybeing substituted by 1 to 5 groups, either identical or different,selected amongst —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR; —NRR′;—NH—COR; Hal (halogen or even perhalogen); —CN: —COOR; —COR; —NO₂;—SO₂OR; with R and R′ representing, independently from each other, alinear, branched or cyclic, saturated or unsaturated hydrocarbonradical, with 1 to 6 carbon atoms, optionally being halogenated or evenperhalogenated; said R and R′ radicals being able to form together withN a carbon ring with 5 to 6 ring members optionally comprising furtherat least one heteroatom selected amongst O, N and/or S in the ringand/or optionally substituted by 1 to 5 groups, identical or different,selected amongst —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″;—NH—COR″; -Hal (halogen); —CN; —COOR″; —COR″; with R″ representing alinear, branched or cyclic, saturated or unsaturated hydrocarbon radicalhaving 1 to 6 carbon atoms, optionally being halogenated, evenperhalogenated; B is a linear or branched, saturated or unsaturatedhydrocarbon radical having 1 to 18 carbon atoms, optionally substitutedby 1 to 5 groups, either identical or different, selected amongst —OH;—OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR; —NRR′; —NH—COR; Hal (halogenor even perhalogen); —CN; —COOR; —COR; —NO₂—; —SO₂OR; with R and R′representing, independently from each other, a linear, branched orcyclic, saturated or unsaturated hydrocarbon radical having 1 to 6carbon atoms, optionally being halogenated or even perhalogenated; saidR and R′ radicals being able to form together with N a carbon ring with5 to 6 ring members optionally comprising further at least oneheteroatom selected amongst O, N and/or S in the ring and/or optionallysubstituted by 1 to 5 groups, identical or different, selected amongst—OH; —OR″; —O—COR″; —SH; —SR; —S—COR″; —NH₂; —NHR″; —NH—COR″; -Hal(halogen); —CN; —COOR″; —COR″; with R″ representing a linear, branchedor cyclic, saturated or unsaturated hydrocarbon having 1 to 6 carbonatoms, optionally being halogenated or even perhalogenated; the Xradical is a radical selected amongst —OH; —OR₄; —NH₂; —NHR₄; —NR₄R₅;—SR₄; —COOR₄; —COR₄; with R₄ and R₅ representing, independently fromeach other, a linear, cyclic or branched, saturated or unsaturatedhydrocarbon radical having 1 to 6 carbon atoms, optionally substitutedby 1 to 5 groups, identical or different, selected amongst —OH; —OR;—O—COR; —SH; —SR: —S—COR; —NH₂; —NHR; —NH—COR; -Hal (halogen, evenperhalogen); CN; —COOR; —COR; with R and R′ representing, independentlyfrom each other, a linear, branched or cyclic, saturated or unsaturatedhydrocarbon radical having 1 to 6 carbon atoms, optionally beinghalogenated or even perhalogenated; said R and R′ radicals being able toform together with N a carbon ring with 5 to 6 ring members optionallycomprising further at least one heteroatom selected amongst O, N and/orS in the ring and/or optionally substituted by 1 to 5 groups, identicalor different selected amongst —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″;—NH₂; —NHR″; —NH—COR″; -Hal (halogen); —CN; —COOR″; —COR″; with R″representing a linear, branched or cyclic, saturated or unsaturatedhydrocarbon radical having 1 to 6 carbon atoms, optionally beinghalogenated or even perhalogenated; said R₄ and R₅ radicals being ableto form together with N a carbon ring with 5 to 6 ring membersoptionally comprising further at least one heteroatom selected amongstO, N and/or S in the ring and/or optionally substituted by 1 to 5groups, identical or different, selected amongst —OH; —OR″; —O—COR″;—SH; —SR″; —S—COR″; —NH₂; —NHR″; —NH—COR″; -Hal (halogen); —CN; —COOR″;—COR″; with R″ representing a linear, branched or cyclic, saturated orunsaturated hydrocarbon radical having 1 to 6 carbon atoms, optionallybeing halogenated or even perhalogenated; the mineral or organic acidsalts thereof, the optical isomers thereof, in an isolated form or as aracemic mixture.
 3. A composition according to claim 2, wherein thecompound of the formula (I) is such that: the Y radical representsoxygen, and/or the R₁ radical represents hydrogen or a linear orbranched, saturated or unsaturated hydrocarbon radical having 1 to12,more particularly 1, 2, 3, 4, 5 or 6 carbon atoms, optionallysubstituted, and/or the R₁ substituants are selected amongst —OH; —OR;and/or —P(O)—(OR)₂ with R representing a linear, branched or cyclic,saturated or unsaturated hydrocarbon radical having 1 to 6 carbon atoms,optionally being halogenated, even perhalogenated; and/or the R₂ radicalrepresents a linear, branched or cyclic, saturated or unsaturatedhydrocarbon radical having 1 to 12, more particularly, 1, 2, 3, 4, 5 or6 carbon atoms, optionally substituted, and/or the R₂ substituants areselected amongst —OH and —OR with R representing a linear, branched orcyclic, saturated or unsaturated hydrocarbon radical having 1 to 6carbon atoms, optionally being halogenated, even perhalogenated; and/orthe R₃ radical represents a radical of the formula —C₆H_((5-y))-B_(y′),where y′=1, 2 or 3; or a radical of the formula -A-C₆H_((5-y))-B_(y)where y=0, 1 or 2; and/or the A radical of R₃ is a linear or branched,saturated or unsaturated hydrocarbon divalent radical having 1 to 12carbon atoms, optionally substituted; and/or the B radical of R₃ is alinear or branched, saturated or unsaturated hydrocarbon radical having1 to 12 carbon atoms, optionally substituted; and/or the substituantsfor A and/or for B are selected amongst -Hal (halogen, even perhalogen);—CN; —COOR, —NO₂; —SO₂—OR; with R representing a linear, branched orcyclic, saturated or unsaturated hydrocarbon radical having 1 to 6carbon atoms, optionally being halogenated, even perhalogenated and/orthe X radical represents a radical selected amongst —OH or —OR₄ with R₄representing a linear, cyclic or branched, saturated or unsaturatedhydrocarbon radical having 1 to 6 carbon atoms, optionally substituted,and/or the R₄ substituants of X are selected amongst —OH or —OR with Rrepresenting a linear, cyclic or branched, saturated or unsaturatedhydrocarbon radical having 1 to 6 carbon atoms, optionally beingsubstituted, even perhalogenated.
 4. A composition according to claim 2or 3, wherein the compound of the formula (I) is such that: the R₁radical represents a methyl, ethyl, propyl or isopropyl radical,optionally substituted by a —OH or —P(O)—(OH)₂ group with R representingmethyl, ethyl, propyl or isopropyl; and/or the R₂ radical represents amethyl, ethyl, propyl, isopropyl, n-butyl, ter-butyl or isobutylradical; and/or the R₃ radical represents a group selected amongst oneof the following formulae:

where the divalent A radical is a methylene, ethylene, propylene and/orthe B radical is a methyl, ethyl, propyl or isopropyl radical,substituted by one or more halogens, in particular, chlorine, bromine,iodine or fluorine, and preferably totally halogenated (perhalogenated),such as perfluorinated, more particularly the (CF₃) perfluoromethylradical, the X radical represents a radical selected amongst —OH, —OCH₃,—OC₂H₅, —O—C₃H₇ or —OC₄H₉.
 5. A composition according to any one ofclaims 2 to 4, wherein the compound of formula (I) is selected amongstthe following compounds:{2-[acetyl-(3-trifluoromethyl-phenyl)-amino]-3-méthyl-butyrylamino}aceticacid,{2-[acetyl-(3-trifluoromethyl-phenyl)-amino]-3-méthyl-butyrylamino}ethylacetate, [2-(acetyl-benzyl-amino)-3-méthyl-butyrylamino]acetic acid,[2-(acetyl-benzyl-amino)-3-méthyl-butyrylamino]ethyl acetate, and(2-{benzyl-[(diethoxy-phosphoryl)-acetyl]-amino}-3-méthyl-butyryl-amino]ethylacetate.
 6. A composition according to any one of preceding claims,wherein the elastase inhibiting compound from the N-acylaminoamidefamily is present in an amount ranging from 0.00001 to 20% by weightbased on the total weight of the composition, preferably from 0.0001 to5% by weight.
 7. A composition according to any one of preceding claims,characterized in that the metalloproteinase inhibitor is selectedamongst an inhibitor of the activity and/or the expression and/or thesynthesis of metalloproteinases selected amongst MMP-1, MMP-2, MMP-3,MMP-7, MMP-9, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-16 and MMP-17.8. A composition according to any one of claims 1 to 6, characterized inthat the metalloproteinase inhibitor is a tissue inhibitor ofmetalloproteinases (TIMP) such as the peptides known under the namesTIMP-1, TIMP-2, TIMP-3 and TIMP4.
 9. A composition according to any oneof claims 1 to 6, characterized in that the metalloproteinase inhibitoris from natural or synthetic origin.
 10. A composition according to anyone of claims 1 to 6, characterized in that the metalloproteinaseinhibitor is selected amongst adapalene or analogous peptides and/orderivatives of Batimastat, Marimastat and/or carotenoids and/orsunscreens and/or vitamin C and/or isoflavones.
 11. A compositionaccording to any one of claims 1 to 6, characterized in that themetalloproteinase inhibitor is selected amongst retinol and thederivatives thereof or retinoic acid and the derivatives thereof orgenistein or daidzein or lycopene.
 12. A composition according to anyone of preceding claims, characterized in that the metalloproteinaseinhibitor preferably represents from 10⁻¹² to 5%, more preferably from10⁻¹⁰ to 2% of the total weight of the composition.
 13. A compositionaccording to any one of preceding claims, having the form of a cosmeticor dermatological composition, designed for caring and/or treatingulcerated areas or having been subjected to a cutaneous stress ormicrostress, more particularly, generated by an exposure to the UVand/or the contact with an irritating product.
 14. A compositionaccording to any one of claims 1 to 12, exhibiting the form of: a care,treatment, cleaning or protection product, of the face or body skin,including the scalp, such as a (day, night, hydrating) care compositionfor the face or the body; an anti-wrinkle or anti-ageing composition forthe face; a mating composition for the face; a composition for theirritated skins; a sun protective, artificial sun tanning (self-tanning)or after-sun care composition; a capillary composition, moreparticularly, a sun protective cream or gel; a scalp care composition,including a hair restoring or hair growth composition; a face skin, bodyor lip make-up product, such as a foundation cream, a tinted cream, acheek or eyelid make-up product, a free or compact powder, an antieye-ring stick, a concealing stick, a lipstick, a lip care product; anda mouth hygiene product, such as a tooth-paste or a mouthwash lotion.15. A composition according to any one of claims 1 to 12, having theform of a face skin care composition, of the anti-wrinkle or anti-ageingtype, or a sun protective or after-sun composition.
 16. A method forcosmetically treating the body or the face skin, including the scalp,wherein a cosmetic composition such as defined in any one of claims 1 to15 is applied onto the skin.